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iinited States Patent M PREPARATION OF BENZO(a)QUINOLIZINES Harry TaconOpenshaw and Norman Whittaker, London,

England, assignors t0 Burroughs Wellcome & Co.

$15158.) Inc., Tuckahoe, N.Y., a corporation of New or No Drawing. FiledJan. 19, 1959, Ser. No. 787,389 Claims priority, application GreatBritain Ian. 22, 1958 Claims. (Cl. 260289) The present invention relatesto the preparation of 111)- benzo(a)quinolizines. The numbering of thisring system is shown in the Formula I.

It has been found that the Mannich base'UI) derived from al:213:4-tetrahydroisoquinoline is oxidized by a suitable oxidizing agentto give a 1:2:3z4z6z7-hexahydro- 2-oxo-1l b-benzo(a)quinolizine (III).This provides a new method for the preparation of compounds containingthe benzo(a)quinolizine ring system.

In these and subsequent formulae R is an alkyl or aryl group, R is ahydrogen atom or an alkyl group, and When R is a hydrogen atom R mayalso be ahydrogen atom. The isoquinoline ring system in the base (II)may carry one or more substituents in the benzene ring when thebenzo-(a)quinoline (III) produced will be correspondingly substituted.

The oxidation of the Mannich base (II) to the benzo- (a)quinolizine(III) is effected by any agent capable of oxidizing a 2-substitutedl:2:3:4-tetrahydroisoquinoline to the corresponding3:4-dihydroisoquinolinium salt. Convenient examples of such agents aresolutions of mercuric acetate, ferric chloride, chlorine, bromine oriodine.

The bases of Formula II are novel compounds and are prepared bya.Mannich reaction of a 1:213:4-tetrahydr0- rated,

3,009,918 Patented Nov. 21, 1961 2 isoquinoline with formaldehyde and aketone (IV) or ketoacid (V).

(II -H2O H200 NE N--CH1 Rtom omm R'-CH2 CH-R O i (IV) I o I-CO2 H2O H100*P 1 NH N-TH: montoorta 122-052 0-12 OOOOH 3 00011 (v) r o When in theketone (IV) R is an aryl group, or R is a methyl group and R is ahydrogen atom, the reaction gives the Mannich base.(II) as shown.

When in the ketone (IV) R is an alkyl group other than a methyl groupand R is hydrogen, the Mannich reaction occurs at either methylenegroupadjacent to the keto group, and the product contains in addition to thebase (11) an isomeric compound in which the groups R and R areinterchanged. The latter isomer does not form a benzo(a)quinolizine onoxidation, and does not fall within the present invention. The isomersmay be separated, or the unseparated mixture may be oxidized and thebenzo(a)quinolizine (III) isolated from the product.

When in the ketone (IV) R 'and R are both alkyl groups butare not thesame, the Mannich reaction pro-- duces a-mixture of tWo isomeric bases(II) both within the present invention. The bases may be separated, orthe unseparated mixture may be oxidized and the two isomericbenzo(a)quinolizines (III) formed may be sepa- The isomeric Mannichbases or the isomeric benzo(a)- quinolizine-s are conveniently separatedfrom each other by fractional crystallization'of suitable salts such asthe naphthailene-Z-sulphonates.

When the keto acid (V) is used, only one Mannich sponding- 3:4-dihydroisoquinolinium salt.

I cerned.

Example 1 A stirred suspension of1:2:3:4-tetrahydro-6:7-dimethoxyisoquinoline hydrochloride (100 g.) inmethyl n-propyl ketone (555 ml.) and aqueous formaldehyde (38.8% W./v.)(37 ml.) was heated to reflux temperature during 10 minutes, and thenheated under reflux for 40 minutes. The solution was cooled, and theresulting mass of crystals treated with suflicient water to dissolve thecrystals. The supernatant layer of ketone was then removed byevaporation under reduced pressure, and the residual aqueous liquiddiluted with water to 1500 ml.

Glacial acetic acid (200 ml.) and mercuric acetate (277.5 g.) wereadded, and the stirred mixture was maintained at 70-75 C. for 30minutes. The suspension of mercurous salts was then cooled, saturatedwith hydrogen sulphide, and filtered through kieselguhr. The aqueousfiltrate was concentrated to half its bulk in vacuo, made alkaline withan excess of potassium hydroxide and extracted with ether. The etherealsolution was washed with water, dried over anhydrous sodium sulphate,and evaporated. A solution of the residual gum in acetone was treatedwith a slight excess of a concentrated solution ofnaphthalene-Z-sulphonic acid in acetone, and then set aside for severaldays. The mixture of naphthalene- Z-sulphonates was collected and theacetone liquors were concentrated-yielding a further crop of mixture.The combined solid was heated under reflux with acetone (2200 ml.) for30 minutes, and filtered. The solid was 3 ethyl 1:2:3 :4:6:7 hexahydro9: 10 dimethoxy 2- oxo-l lbbenzo(a quinolizine naphthalene-2-sulphonate,melting point 198-199 C. with efiervescence.

The acetone liquors were evaporated to dryness and the residue wascrystallized from water, giving 2-(hex-3- onyl) 1:2:3 :4 tetrahydro 6:7dimethoxyisoquinol-ine naphthalene-Z-sulphonate, melting point 140-143C. Evaporation of the aqueous liquors. to dryness in vacuo gave'amixture of the above two salts from which a further amount of thebenzo('a)quinolizine naphthalene-L sulphonate was isolated in the manneralready described.

The free base, 3-ethyl-1:2:3:4:6:7 hexahydro 9:10- dimethoxy-Z-oxo-l1bbenzo(a) quinolizine, melting point 110-111 C., was obtained by treatinga hot aqueous sus pension of its naphthalene-2-sulphonate with aqueousptassium hydroxide, or with aqueous ammonia.

Example 2 Using the methods described in Example 1, 1:2:324-tetrahydro-6:7-dimethoxyisoquinoline hydrochloride (10 g.)., diethylketone (55 ml.), and aqeuous formaldehyde (38.8% w./v.) (3.7 ml.) werereacted together, and the product was oxidized with mercuric acetate(27.75 g.) in the presence of acetic acid, yielding1:2:3z4z6z7-hexahydro 9: l0 dimethoxy 1:3 dimethyl 2- oxo11bbenzo(a)quinolizine naphthalene-Z-sulphonate, melting point 174175 C.with etfervescence. Recrystallization from ethanol gave the purenaphthalene-2-sulphonate, melting point 185-187 C. with efiervescence.The free base, obtained by the method of Example 1, meltedat l03-104 C.

Example 3 A stirred suspension of 1:2:3:4-tetrahydro-6z7-dimethoxyisoquinoline hydrochloride g.) in benzylmethyl ketone (14.6 g.) and aqueous formaldehyde (38.8% w./v.) (1.77ml.) was heated during 15 minutes to 100 C. and then maintained at 100C. for 40 minutes. The solution was cooled, the resulting suspension ofcrystals shaken with water (150 ml.), and the excess ketone removed byextraction with ether. The aqueous liquid was concentrated to 75 ml. invacuo, and then heated with mercuric acetate (13.87 g.) and glacialacetic acid ml.) in the manner of Example 1. An ethereal solution of thecrude product was concentrated to small bulk and set aside, giving1:2:3:4:6:7-hexahydro-9:IO-dimethoxy- Example 4 An ice-cold solution ofpotassium hydroxide (3.36 g.) in water (45 ml.), and ethyla-ethylacetoacetate (8.6 g.) were shaken together for 1 hour, and thenset aside overnight at room temperature. The resulting solution wascooled to 0 C., brought to pH 5-6 with concentrated hydrochloric acid,and treated with 1:2:324-tetrahydro- 6:7-dimethoxyisoquinolinehydrochloride (10 g.) and aqueous formaldehyde (38.8% w./v.) (3.37 ml.).The stirred solution was kept at 0 C. and, by periodic addition ofconcentrated hydrochloric acid, was brought from pH 6 to pH 3 during 2hours. The solution was then set aside at room temperature overnight,and heated in vacuo to remove some methyl n-propyl ketone present. Theres idual aqueous solution was diluted to ml. with water, heated withmercuric acetate (27.75 g.) and glacial acetic acid (20 ml.) and workedup in the manner of Example 1, yielding 3-ethyl-l :2: 3 :4: 67-hexahydro-9: IO-dimethoxy- Z-oxo-l lb-benzo (a) quinolizinenaphthalene-2-sulphonate, melting point 198-199 C. with eifervescence.

Example 5 Ethyl a-ethylacetoacetate (138 g.) was hydrolyzed with 0.93N-potassium hydroxide (1034 ml.) and then reacted with 1 :2 z 3:4-tetrahydro-6 7 -dimethoxyisoquinoline hydrochloride (200 g.) andaqueous formaldehyde (38.8% w./v.) (67.4 ml.), in the manner of Example4. The aqueous solution of Mannich base was diluted with water to 3000ml., then heated with mercuric acetate (555 g.) and glacial acetic acid(400 ml.), and worked up in the manner of Example 1, yielding3-ethyl-1:2:3:4:6:7-hexahydro 9: 10 dimethoxy 2 oxo 11b hem-0(a)quinolizine naphthalene-2-sulphonate, melting point 198199 C. withefiervescence.

Example 6 1:2:3:4:6:7 hexahydro 9:10 dimethoxy 2 0x0- 3 n propyl 11bbenzo(a)quino lizine naphthalene- 2-sulphonate, melting point -179 C.with eifervescence, was prepared by the method of Example 4 from ethyla-n-propylacetoacetate (15 g.) and1:223:4-tetrahydro-6:7-dimethoxyisoquinoline hydrochloride (20 g.).Recrystallized from ethanol, the product melted at 186- 187 C. withetfervescence. The free base melted at 107-108 C.

Example 7 3 n -butyl-1:2:3:4:6:7 hexahydro 9:10 dimethoxy 2 -'oxo 11bbenzo(a)quinolizine naphthalene 2- sulphonate, melting point 207-208 C.with eifervescence, was prepared by the method of Example 4 [theby-product, methyl n-amyl ketone, being removed by ether-extraction]from ethyl a-n-butyl-acetoacetate 10.15 g.) and 1 :2 3 :4tetrahydro-67-dimethoxyisoquin0line hydrochloride (10 g.). The free base melted atIll-112 C.

Example 8 Ethyl u-n-amylacetoacetate (21.8 g.) was shaken mechanicallyfor 5 hours with 0.87 N-potassium hydroxide (138 ml.), and then reactedwith 1:2:3z4-tetrahydro-6z7- dimethoxyisoquinoline hydrochloride (20 g.)and aqueous formaldehyde (38.8% w./v.) (6.74 ml.) and oxidized withmercuric acetate by the method of Example 7. The prodduct, 3 namyl-1:2:3:4:6:7 hexahydro 9:10 dimethoxy 2 oxo- 11b benzo(a)quinolizine naphthalene-2-sulphonate, melted at 200-202" C. The freebase had melted at 121-422 C.

Example 9 1 :2 z 3 :4-tetrahydro-6 7 -dimethoxyisoquinolinehydrochloride (20 g.) was reacted with aqueous formaldehyde (38.8%w./v.) (7.4 ml.) and methyl-n-propyl ketone (111 ml.) in the manner ofExample 1. To an aqueous solu- The crystals which separated 'werecollected, washed with water, pressed as dry as possible, and dissolvedin hot acetone (75 ml.). Cooling the acetone solution to C. gavecrystals of 2-(hex-3-onyl)-1z2z3z4-tetrahydro- 6 7-dimethoxyisoquinolinenaphthalene-Z-sulphonate of melting point l38141 C. Recrystallizationfrom acetone gave the pure salt, melting point 145l46 C. The free basemelted at 37.538.5 C.

The above aqueous liquors Were made alkaline with potassium hydroxide,extracted with chloroform, and the extract was washed with water, driedover anhydrous sodium sulphate, and evaporated. The residual gum wasdissolved in acetone, neutralized with a solution ofnaphthalene-Z-sulphonic acid in acetone, seeded, and set aside at 0 C.for several days. The resulting crystals of 2-(2-ethylbut-3-onyl)-1:2:3:4-tetrahydro 6:7 dimethoxyisoquinolinenaphthalene-Z-sulphonate, melted at 136l40 C. Recrystallization fromacetone gave pure material, melting point 144-145 C. Admixture with thenaphthalene-Z-sulphonate of the isomeric 2-(hex-3-onyl)isoquinolinederivative depressed the melting point to 129- 141. C.

Example 10 An aqueous solution of Mannich base, obtained from ethylot-ethylacetoacetate (6.9 g.) and 122:3:4-tetrahydro-6:7-dimethoxyisoquinoline hydrochloride (10 g.) by the method of Example5,- was made alkaline with aqueous potassium hydroxide andextracted'with chloroform. The extract was washed with water, dried overanhydrous sodium sulphate, and evaporated. The residual gum wasdissolved in acetone, neutralized with a strong solution ofnaphthalene-2-sulphonic acid in acetone, and then seeded withl:2:3:4-tetrahydro-6:7-dimethoxyisoquinoline naphthalene-Z-sulphonate.After standing at room temperature the crystals of this substance,melting point 188-191 C., were collected and discarded. The motherliquors were concentrated to 30 ml., scratched to induce crystallizationand set aside at 0 C. for 2 days. Crystals of 2-(2-ethylbut-3-onyl)1:2:3:4-tetrahydro-6:7-dimethoxyisoquinoline naphthalene-2-sulphonate,melting point 140-142 C., separated. Recrystallized from acetone, thismelted at 144145 C. alone and in admixture with the second product ofExample 9.

xample 11 2 (2 ethylbut 3 onyl) 1:2:324 tetrahydro-6:7-dimethoxyisoquinoline naphthalene-Z-sulphonate (2 g.) was shakenwith chloroform (25 ml.), water (50 ml.) and N-aqueous potassiumhydroxide ml.). The chloroform layer was separated, washed with water,and evaporated under reduced pressure. The residual gum was dissolved inWater (50 ml.) containing glacial acetic acid (3 ml.) and then heatedwith mercuric acetate (2.56 g.) at 70-75 C. for 30 minutes. The reactionmixture was worked up in the manner of Example 1, yielding 3-ethyl-1:2:3:4:6:7 hexahydro 9:10 dimethoxy 2 oxo- 1lb-benzo(a)quinolizinenaphthalene-Z-sulphonate, melting point 197-198 C. with efiervescence.

Example 12 122:3:4 tetrahydro 6:7 dimethoxyisoquinoline hydrochlorideg.), ethyl methyl ketone (47 ml.) and aqueous formaldehyde (38.8% w./v.;3.54 ml.) were heated together in a sealed tube at 100 C., with shakinguntil solution occurred, for 30 minutes. The reaction solution wascooled, treated With water (100 ml.), and the excess ketone wasevaporated under reduced pressure. The residual aqueous solution wascooled to 0 C. and made alkaline with potassium hydroxide, yieldingcrystals of 1:2:3 :4-tetrahydro 6:7dimethyl-2-(2-methylbut-3-onyl)isoquinoline, melting point 9798 C.

Example 13 Ethyl a-methylacetoacetate (12.55 g.) was hydrolyzed with0.93 N-potassium hydroxide (103 ml.) and then reacted with 1 22:3:4-tetrahydro-6;7-dimethoxyisoquinoline hydrochloride (20 g.) andaqueous formaldehyde (38.8% w./v.) (6.74 ml.) in the manner of Example4. The aqueous solution of Mannich base thus obtained was made alkalinewith potassium hydroxide, yielding 122:3: 4 tetrahydrc- 6:7 dimethoxy 2(2 methylbut 3 onyl)isoquinoline, melting point 97-98" C.

Example 14 A mixture of 1:213:4-tetrahydro-6:7-dimethoxy-2-(2-methylbut-3-onyl)isoquinoline (1 g.), mercuric acetate (4.6 g.), waterml.) and glacial acetic acid (5 ml.) was heated under reflux for 20minutes. The cooled reaction mixture was treated with hydrogen sulphide,filtered through kieselguhr, and the filtrate Was concentrated, madealkaline with potassium hydroxide, and extracted with chloroform. Thechloroform extract was washed with water, dried over sodium sulphate,and evaporated. The residual gum was dissolved in acetone (10 ml.) andneutralized with a solution of naphthalene-2- sulphonic acid in acetone,giving 1:2:3:4:6:7-hexahydro- 9:10 dimethoxy 3 methyl 2 oxo 11b benzo(a)quinolizine naphthalene-2-sulphonate, melting point 200 202 C. witheffervescence. The free base melted at 138- 139 C.

Example 15 A solution of 122:3:4-tetrahydro-6:7-dimethoxy-2-(2-methylbut-3-onyl)isoquinoline (1 g.) and anhydrous potassium'acetate(0.98 g.) in hot anhydrous ethanol (15 ml.) was treated with a solutionof iodine (1.14 g.) in ethanol (15 ml.). The mixture was refluxed for 20minutes, cooled, diluted with water, and the ethanol was removed underreduced pressure. The residual aqueous suspension of product was madealkaline with potassium hydroxide and extracted with chloroform. Thechloroform extract was worked up by the method of Example 14, yielding122:3:41627-hexahydro 9: 10 dimethoxy-3- methyl 2 oxo 11bbenzo(a)quinolizine naphthalene 2-sulphonate, melting point 202 203 C.with effervescence.

Example 16 1 :2 :3 :4-tetrahydro-6 :7 -dimethoxyiso quinoline hydrochloride (10 g.), acetone (38.3 ml.) and aqueous formaldehyde (38.8%w./v.) (3.54 ml.) were heated together in a sealed tube, with frequentshaking, at C. for 25 minutes. After cooling, the mass of crystals wasdissolved in water (ml) and theexcess acetone was evaporated underreduced pressure. The residual aqueous solution was cooled to 0 C., madealkaline with potassium hydroxide, and extracted with chloroform. Theextract was washed with water, dried over sodium sulphate, andevaporated. The residual gum was dissolved in acetone (40 ml.) andneutralized with a strong solution of naphthalene-Z-sulphonic acid inacetone, yielding a mass of crystals of2-(but-3-onyl)-1:2:3:4-tetrahydro-' 6:7-dimethoxyisoquinolinenaphthalene 2 sulphonate,

melting point 167168 C., with efiiervescence.

Example 17 A mixture of 2-(but-3-onyl)-122:3:4-tetrahydro-6z7-dimethoxyisoquinoline naphthalene-2-sulpho-nate (2 g.), mercuric acetate(5.42 g.), Water (35 ml.) and glacial acetic acid (6 ml.) was heatedunder reflux for 20 minutes. The reaction mixture was worked up in themanner of Example 14, yielding the crude product in chloroform solution.The chloroform was evaporated and the residual gum dissolved in hotether (4 ml.), cooled, and set aside at 0 C., giving crystals of1:2:3:4:6:7-hexahydro 9: 10 dimethoxy 2 oxo 11=b benzo(a)quinolizine,melting point 146l50 C. Recrystallized from light petroleum (boilingrange 60-80 C.), the product melted at l52153 C.

Example 18 1:2:3:4-tetrahydroisoquinoline hydrochloride (20.9 g.), ethylmethyl ketone (132 ml. and aqueousfor-maldehyde (38.8% w./V.) (10 ml.)were heated together in a sealed tube, with shaking until solutionoccurred, at 100 C. for 20 minutes. The cooled reaction solution wasevaporated and the residual oil shaken vigorously with acetone (2001111.). The resulting crystals of 1:2:3:4-tetrahydro-2-(2-methylbut-3-onyl)isoquinoline hydrochloride melted at 150-151 C. withetfervescence.

Example 19 A mixture of 1:2:3z4-tetrahydro-2'(2-methylbut-3-onyl)isoquinoline hydrochloride g), mercuric acetate (25.2 g), Water(164 ml.) and glacial acetic acid (27 ml.) was heated under reflux forminutes. The reaction mixture was worked up in the manner of Example 14,yielding a chloroform solution of crude product. The chloroform wasevaporated and the residual gum was extracted with hot light petroleum(boiling range 60-80 C.) (200 ml.). The extract was evaporated, and theresidual material was dissolved in benzene and poured down a column ofactivated alumina, eluting the column with benzene. The benzene solutionof product was evaporated, and the residual solid dissolved in acetoneand treated with ethereal hydrogen chloride, giving 122:3 :4:6:7hexahydro 3 methyl-Z-oxo-l1-b-benzo(a)- quinolizine hydrochloride,melting point 246-247 C. with efiervescence. The free base melted at95-96 C.

Example 1 f2 3 :4-tetrahydro-2- 2-methyl-but-3-onyl) 6 7methylenedioxyisoquinoline hydrochloride, melting point 164-165" C. withetfervescence, was prepared by the method of Example 18 from1:2:3:4-tetrahydro-6:7- methylenedioxyisoquinoline hydrochloride (20.g.), methyl ethyl .ketone (100.5 ml.) and aqueous formaldehyde (38.8%W./v. (7.6.ml.').

Example 21 A mixture of 1:2:3z4-tetrahydro-2-(2-methyl-but-3- onyl) 6:7methylenedioxyisoquinoline hydrochloride (4 g), mercuric acetate (17.1g.), Water (112 ml.) and glacial acetic acid (19 ml.) was heated underreflux for 10 minutes. The cooled reaction mixture was Worked up in themanner of Example 14 yielding a chloroform solution of crude product.The choloroform was evaporated and the residual gum was refluxed withether (20 ml.) yielding crystals of 1:2:3 :4:6:7 hexahydro 3methyl-9:10- methylenedioxy-Z-oxo-l lb benzo(a) quinolizine, meltingpoint.l54158 C. Recrystallization from ethanol gave the pure base,melting at 157l58 C.

Isoquinoline derivatives of the Formula II and benzo(a)quinolizinederivatives of the Formula III are valuable as chemical intermediates,for example for the synthesis of emetine and emetine analogues.Benzo(a)- quinolizine compounds of the Formula III have also been shownto possess sedative actions.

What we claim is:

l. A compound selected from the class consisting of the isoquinolinecompounds of the formula GH .13 l

1 N-CH:

and the acid addition salts thereof, in which formula R and R are eachselected from the class consisting of the hydrogen atom and alkoxylgroups having not more than four carbon atoms and taken together are analkylenedioxy group having not more than four carbon atoms, R has notmore than four carbon atoms and is selected from the class consisting ofthe hydrogen atom and lower alkyl groups, and R has notmore than eightcarbon atoms and is selected from the class consisting of the hydrogenatom and lower alkyl and phenyl groups when R is a hydrogen atom, and isselected from the class consisting of the lower alkyl and phenyl groupswhen R is a lower alkyl radical.

3. 2 (2 ethylbut 3 onyl) 1:2:3:4 tetrahydro 6: 7-dimethoxyisoquinoline.

4. A method for the preparation of isoquinoline compounds of the formulaand the acid addition salts thereof, in which formula B is selected fromthe class consisting of the 1:2-phenylene the lower dialkoxy phenyleneand the corresponding lower alkylenedioxy phenylene groups, R isselected from the class consisting of the hydrogen atom and lower alkylgroups, and R is selected from the class consisting of the hydrogen atomand lower alkyl and phenyl groups when R is a hydrogen atom, and isselected from the class consisting of the lower alkyl and phenyl groupswhen R is a lower alkyl group, comprising the reaction of a 1:2:3z4-tetrahydroisoquinoline with formaldehyde and a ketonic compound of theformula wherein X is selected from the class consisting of the hydrogenatom and carboxyl group and R and R have the meaning as defined above.

5. A method for the preparation of benzo(a)quinolizine compounds of theformula CH2 bHz B l and the acid addition salts thereof, in whichformula B is selected from the class consisting of the 1:2-phenylene thelower dialkoxy phenylene and the corresponding lower alkylenedioxyphenylene groups, R is selected from the class consisting of thehydrogen atom and lower alkyl groups, and R is selected from the classconsisting of the hydrogen atom and lower alkyl and phenyl groups when Ris a hydrogen atom, and is selected from the class consisting of thelower alkyl and phenyl groups when R is a lower alkyl group, comprisingthe oxidation of a correspondingly substituted isoquinoline derivativeof the formula using an oxidizing agent capable of oxidizing a2-substituted l:2:3:4-tetrahydroisoquinoline to the corresponding 3:4dihydroisoquinolinium salt.

6. A method for the preparation of benzo(a) quinolizine compounds of theformula and the acid addition salts thereof, in which formula R and Rare each selected from the class consisting of the hydrogen atom andalkoxyl group having not more than four carbon atoms and taken togetherare an alkylenedioxy group having not more than four carbon atoms, R hasnot more than four carbon atoms, and is selected from the classconsisting of the hydrogen atom and alkyl groups, and R has not morethan eight carbon atoms and is selected from the class consisting of thehydrogen atom and alkyl and aryl groups when R is a hydrogen atom, andis selected from the class consisting of the lower alkyl and phenylgroups when R is a lower alkyl radical, comprising the oxidation of acorrespondingly substituted isoquinoline derivative of the formula usingan oxidizing agent capable of oxidizing a 2-substitutedl:2:3:4-tetrahydroisoquinoline to the corresponding 3:4-dihydroisoquinolinium salt.

7. A method for the preparation of 3-ethyl-1:2:3:4:6:7-hexahydro-9:10-dimethoxy-2-oxo-11b benzo(a) quinolizine and acidaddition salts thereof comprising the oxidation of a compound selectedfrom the class consisting of 2-(2-ethylbut-3-onyl) -1 :2 3:4-tetrahydro-6 :7-dimethoxy isoquinoline and the acid addition saltsthereof using an oxidizing agent capable of oxidizing a 2-substituted1:2:3:4-tetrahydroisoquinoline to the corresponding 3:4-dihydroisoquinolinium salt.

8. A method for the preparation of benzo(a)quinolizine compounds of theformula CH: B

R: Rt

and the acid addition salts thereof, in which formula B is selected fromthe class consisting of the 1:2-phenylene the lower dialkoxy phenyleneand the corresponding lower alkylenedioxy phenylene groups, R isselected from the class consisting of the hydrogen atom and lower alkylgroups, and R is selected from the class consisting of the hydrogen atomand lower alkyl and phenyl groups when R is a hydrogen atom, and isselected from the class consisting of the lower alkyl and phenyl groupswhen R is a lower alkyl group, comprising the oxidation of acorrespondingly substituted isoquinoline derivative of the formula usingmercuric acetate.

9. A method for the preparation of benzo( a) quinolizine compounds ofthe formula CH2 B 5 and the acid addition salts thereof, in whichformula B is selected from the class consisting of the 1:2-phenylene thelower dialkoxy phenylene and the corresponding lower alkylenedioxyphenylene groups, R is selected from the class consisting of thehydrogen atom and lower alkyl groups, and R is selected from the classconsisting of the hydrogen atom and lower alkyl and phenyl groups when Ris a hydrogen atom, and is selected from the class consisting of thelower alkyl and phenyl groups when R is a lower alkyl group, comprisingthe oxidation of a correspondingly substituted isoquinoline derivativeof the formula References Iited in the file of this patent UNITED STATESPATENTS Brossi Apr. 15, 1958 Brossi Apr. 15, 1958 UNITED STATES PATENTOFFICE CERTIFICATE OF CORRECTION Patent No. 3,009,918 November 21 1961Harry Tacon Openshaw et al.,

It is hereby certified that error appears in the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below.

Column 1, lines 37 to 4'7 the right-hand formula should appear as shownbelow instead of as in the patent:

Signed and Sealed this 8th day of May 1962:.

(SEAL) Attest:

ERNEST w. SWIDER DAVID ADD Attesting Officer Commissioner of Patents

1. A COMPOUND SELECTED FROM THE CLASS CONSISTING OF THE ISOQUINOLINECOMPOUNDS OF THE FORMULA